Retinoid-related orphan receptors (RORs) constitute a subfamily of nuclear receptors (NR's) that function as ligand-dependent transcription factors. The ROR family comprises three members, namely RORα (ROR-alpha; NR1F1), RORβ (ROR-beta; NR1F2) and RORγ (ROR-gamma; NR1F3). They are termed “orphan” receptors because their endogenous ligands have yet to be agreed upon definitely. RORs exhibit a domain structure typical of nuclear receptors and contain an N-terminal domain, a highly conserved DNA-binding domain (DBD) consisting of two zinc finger motifs, a ligand-binding domain (LBD), and a hinge domain spacing the DBD and LBD (A. M. Jetten et al., Frontiers in Endocrinology Diabetes (2012) 4: 1; L. A. Salt and T. B. Burris, Trends in Endocrinology and Metabolism (2012) 23: 619). RORs recognize and bind as monomers to specific sequences of DNA, termed ROR response elements (ROREs), typically consisting of an AGGTCA site with a 5′ AT-rich extension in the regulatory region of the target gene. When bound to this element within the promoters of that target genes, RORs recruit coactivators, leading to continual activation of transcription of that target genes.
The three RORs display significant sequence similarity and conservation between species. Each ROR gene generates multiple isoforms based on alternative promoter usage and exon splicing, with all of the isoforms varying only in the N-terminal region of the receptor. The RORs display distinct patterns of tissue expression and are involved in the regulation of various physiological processes (L. A. Salt and T. B. Burris, Trends in Endocrinology and Metabolism (2012) 23: 619). For instance in the ROR γ subfamily that consists of ROR γ1 and ROR γ2 (sometimes also referred to as ROR γt) ROR γ1 is expressed in many tissues, including liver, adipose, skeletal muscle, and kidney, while the expression of ROR γ2 is exclusively in a few distinct cell types of the immune system (A. M. Jetten, Nuclear Receptor Signaling (2009) 7: 1). Thus, ROR γ1 and in particular ROR γ2 are important regulators of several diverse immune functions. ROR γ2 plays an important role in the differentiation of naïve T cells into interleukin 17 (IL-17) producing T helper 17 (Th17) cells. Th17 cells are defined by a specific cytokine profile and secrete IL-17, IL-9, IL-21, IL-22, IL-26, and CCL20 (L. A. Salt and T. B. Burris, Trends in Endocrinology and Metabolism (2012) 23: 619). These mediators are responsible for several different effector functions in host defense as well as in autoimmune diseases. While Th17 cells play a significant role in host defense against extracellular pathogens as well as against obligate intracellular pathogens, these cells are also believed to be the major pro-inflammatory cells involved in autoimmunity (A. M. Jetten et al., Frontiers in Endocrinology Diabetes (2012) 4: 1; L. A. Salt and T. B. Burris, Trends in Endocrinology and Metabolism (2012) 23: 619; A. M. Jetten, Nuclear Receptor Signaling (2009) 7: 1). Since overexpression of ROR γ2 in naïve CD4+ T cells was demonstrated to drive the induction and development of those Th17 cells, inhibition of ROR γ with specific synthetic ligands has become a goal for medicinal chemistry in order to provide treatments for reducing autoimmune pathology.
It is also to be noted that ROR γ has been shown to play a role in the development of diabetes, adipositas and insulin resistance (A. M. Jetten et al., Frontiers in Endocrinology Diabetes (2012) 4: 1; L. A. Salt and T. B. Burris, Trends in Endocrinology and Metabolism (2012) 23: 619; A. M. Jetten, Nuclear Receptor Signaling (2009) 7: 1).
L. A. Salt and T. B. Burris, Trends in Endocrinology and Metabolism (2012) 23: 619; A. M. Jetten, Nuclear Receptor Signaling (2009) 7: 1, describe some synthetic ligands modulating the ROR γ activity. None of these synthetic ligands are tetrahydro-tetrazolo[1,5-a]pyrazines.
M. Umkehrer et al., Tetrahedron Lett. 45 (2004) 6421, disclose the synthesis of certain tetrahydro-tetrazolo[1,5-a]pyrazines by a multi-component reaction. In particular they disclose 7-benzyl-8-(4-methoxyphenyl)-5,6,7,8-tetrahydro-tetrazolo[1,5-a]pyrazine. They do not disclose any medicinal or pharmaceutical use or any activity on ROR γ of those compounds.